Mycosis is a disease caused by fungal infection in human and animals. Candidiasis by Candida spp., cryptococcosis by Cryptococcus spp., aspergillosis by Aspergillus spp., zygomycosis by Zygomycetes, dermatophytosis by Trichophyton spp., etc. are known as typical mycoses in human (Pathogenic Fungus and Mycosis (Nanzando, Revised version 2), pp. 42-45; Non-patent Document 1).
Trichophyton sp. is a dermatophyte which can be a causative agent of tinea, and has a property of keratin degradation. Because of this property, it causes tinea by penetrating into skin, nail and hair (Pathogenic Fungus and Mycosis (Nanzando, Revised Version 2), pp. 184-187; Non-patent Document 2).
Tinea unguium is a nail disease caused by dermatophytes, associated with symptoms such as turbidity, thickening, tearing and deformation of nail plates. In Japan, one out of ten, i.e., approximately 12 million people are said to be the patients of the disease. This disease is frequently found in elderly people, and thus there is a concern about a further increase in the number of patients in years to come. There is a report that patients with diabetes are susceptible to this disease, and possibility of causing severe complications is also indicated.
For the treatment of tinea unguium, only oral antifungal agents (itraconazole and terbinafine) are currently approved in Japan. Topical antifungal agents used for common dermatophytosis cannot penetrate into nail keratin or nail bed, and thus they are not expected to be fully effective. Drug interactions, hepatic disorders and side effects by prolonged administration are big concern for oral antifungal agents. Elderly people having a high risk of tinea unguium and patients with diabetes are likely to take a number of medicines. Therefore, it is difficult to administer oral antifungal agents to them for the treatment of tinea unguium (Br. J. of Dermatol., vol. 139(4), p 665, 1998; Non-patent Document 3).
Topical nail lacquer agent such as amorolfine and ciclopirox have been approved and used overseas. Their penetration property into nails, however, is very low, and their further permeation into nail matrix cells cannot be expected. Therefore, their efficacies are weaker than those of the oral medicines. Recently, studies of antifungal agents and formulations intended for improved nail permeability are underway, but no antifungal agents with sufficient nail permeability have been found.
As a compound having the skeleton of 2-(1H-pyrazol-1-yl)phenol, dimethyl-1H-pyrazol-1-yl)phenol having methyl groups at 3-position and at 5-position of the pyrazol ring is known (Annual Report by the Takeda Research Laboratories (1963) 22, p 27; Non-patent Document 4). These are intended to prevent proliferation of Mycobacterium tuberculosis. Non-patent Document 4 has no disclosure of 2-(1H-pyrazol-1-yl)phenol compounds other than 2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol.
As the other compounds having the skeleton of 2-(1H-pyrazol-1-yl) phenol than 2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol, 2-(1H-pyrazol-1-yl)phenol, 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1,4-benzene diol, 2-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-1,4-benzene diol and the like are known. These are used for various chemical reactions and as a material for an electroluminescence element compound (Japanese Patent No. 4284169: Patent Document 1) and a light stabilizer (Spanish Laid-open Patent Publication No. 2015648: Patent Document 2) or the like.
Further, WO 2003/005999 (Patent Document 3) discloses 2-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-5-methylphenol.
These prior art documents neither suggest nor disclose the anti-Trichophyton activity of compounds having the skeleton of 2-(1H-pyrazol-1-yl)phenol.